PROJECT SUMMARY Inflammatory bowel disease (IBD) is a chronic inflammatory condition that affects a growing number of people in the United States and for which there is no cure. IBD is characterized by diarrhea, pain, oxidative stress and reactive oxygen species (ROS), and increased risk of colon cancer. There is a great need to develop better treatments for IBD, especially treatments that act locally in the inflamed colon without whole-body exposure and associated side effects. The goal of this proposal is to develop innovative anti-inflammatory beads for improved treatment of IBD. The anti-inflammatory beads are designed to be given orally to the patients and engineered to find and preferentially localize to the inflamed parts of the colon, where they respond to signals associated with the colon inflammation and ROS to activate their therapeutic function. Because of their properties, the distribution of the beads is restricted to the colon and they are not absorbed into the whole body like conventional IBD drugs, thus minimizing undesired side effects during long-term chronic treatment. This project is based on our recent discoveries and development of novel type of materials (PCQ) based on a widely used antimalarial drug chloroquine. The overall objective of this proposal is to develop, and test oral non-absorbable therapeutic particles designed to preferentially accumulate in, and safely reduce, colon inflammation in IBD. The central hypothesis of this proposal is that reformulation of PCQ as inflammation-sensitive beads will lead to improved accumulation in the inflamed parts of the colon and result in improved anti-inflammatory activity in IBD. The hypothesis is based on (i) available evidence that orally given nano- and microparticles preferentially localize at the IBD inflammation sites and (ii) our current studies, which demonstrate that PCQ alone enhances healing of experimental IBD in mice. The use of inflammation-responsive particles to deliver therapeutically active polymer (PCQ) represents an innovative approach to the local oral treatment of IBD. We will accomplish the overall objectives by pursuing three specific aims. In Aim 1, we will prepare ROS-responsive particles based on therapeutic PCQ. In Aim 2, we will validate the efficacy of the optimized PCQ particles in epithelial injury model of IBD, infectious model of IBD, and in a chronic IBD model induced by the transfer of activated T cells. In Aim 3, we will determine the cellular and molecular modalities affected by the PCQ treatment.